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Schizophrenia is a severe neuropsychiatric disorder associated with significant disability. The antipsychotic drugs, the mainstay of treatment, are only effective in a proportion of patients. For those who do not respond, so-called treatment refractory schizophrenia (TRS) patients, the only available treatment is the atypical antipsychotic drug, clozapine. Although it has singular efficacy in treating TRS patients its use is restricted and delayed due to rare and potentially fatal side effects. Ability to predict response can help identify potential responders and introduce treatment early, but studies have so far not been able to identify any clinically useful biomarkers of response. A system that has been implicated in both schizophrenia and mechanism of action of clozapine is the epidermal growth factor (EGF) system. This study sought to examine the EGF system for potential predictors of response and did so by measuring peripheral EGF and betacellulin (BTC) levels in a prospective cohort of TRS patients commencing clozapine treatment. It also examined a larger cross-sectional sample of long-term clozapine treated patients for potential associations with EGF system single nucleotide polymorphisms (SNPs). The prospective sample of TRS patients were followed up over twenty-six weeks and clinical data and blood samples were collected at set time points. Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS). Additional clinical information was gathered using the Clinical Global Impression – Severity (CGI-S) scale, Global Assessment of Functioning (GAF) scale, Simpson Angus Scale (SAS) and the Calgary Depression Scale (CDS). Both EGF and BTC levels were determined using commercially available enzyme linked immuno-sorbent assay (ELISA) kits. Of the sixty-four patients who consented for the prospective study sixty entered the study and forty-nine completed the twenty-six weeks of clozapine treatment. Socio-demography of the patients reveale